Diabetes mellitis denotes a spectrum of metabolic diseases characterized by abnormally high blood glucose levels. There are two major types of diabetes. Type 1 diabetes results from the body's failure to produce insulin. For these patients, administration of insulin is the only available therapy. Type 2 diabetes typically begins with insulin resistance, a condition in which the body's cells fail to respond to insulin. As the disease progresses, a relative or absolute lack of insulin production also develops. Type 2 diabetes is often associated with excessive body weight and lack of exercise. The treatment for Type 2 diabetes typically starts with exercise and diet management as well as medications without insulin. As the disease deteriorates, many patients with Type 2 diabetes eventually require insulin therapy to support their metabolism.
In healthy individuals, insulin secretion is closely tied to blood glucose level. Increased glucose level, for example, after meals, is compensated by a rapid increase in insulin release within minutes of glucose entry into the blood. In the fasting state, insulin level falls to a basal level, which is sufficient to guarantee a continuous supply of glucose to insulin-sensitive organs and tissues. The objective of insulin therapy is to replicate this natural time-action profile of insulin in diabetic patients, such that blood glucose level can stay within the normal range characteristic of healthy individuals. However, current insulin products and delivery systems do not sufficiently meet this objective due to limitations in the absorption of the insulin or insulin analogue.
For example, when insulin is solubilized in a buffer without zinc and stored at room temperature (25-30° C.), the insulin will begin to form amyloid fibrils within 7-14 days. To avoid this problem, currently available insulin products are typically formulated with zinc, which forms a complex with insulin called a zinc-insulin hexamer. Zinc-insulin hexamers can be stable in solution at room temperature for greater than 30 days, which is long enough to meet regulatory requirements for insulin formulation stability. However, zinc-insulin hexamers are too large to be readily absorbed by capillaries, and so the hexamers must disassemble after injection before the insulin can be absorbed. This prevents these formulations from being absorbed quickly enough.
Accordingly, there is an unmet need for insulin compositions, formulations, and delivery systems that better replicate the natural time-action profile of insulin.